The treatment of infected surface or subsurface lesions in patients has typically involved the topical or systemic administration of anti-infective agents to a patient. Antibiotics are one such class of anti-infective agents that are commonly used to treat an infected abscess, lesion, wound, or the like. Unfortunately, an increasingly number of infective agents such as bacteria have become resistant to conventional antibiotic therapy. Indeed, the increased use of antibiotics by the medical community has led to a commensurate increase in resistant strains of bacteria that do not respond to traditional or even newly developed anti-bacterial agents.
For example, Staphylococci are known to be significant pathogens that cause severe infections in humans, including endocarditis, pneumonia, sepsis and toxic shock. Methicillin resistant S. aureus (MRSA) is now one of the most common causes of nosocomial infections worldwide, causing up to 89.5% of all staphylococci infection. Community outbreaks of MRSA have also become increasingly frequent. The main treatment for these infections is the administration of glycopeptides (Vancomycin and Teicoplanin). MRSA have been reported for two decades, but emergence of glycopeptide-resistance in S. aureus—namely glycopeptide intermediate (GISA) has been reported only since 1997.22 The glycopeptides are given only parenterally, and have many toxic side effects. The recent isolation of the first clinical Vancomycin-resistant strains (VRSA) from a patient in USA has heightened the importance and urgency of developing new agents. Even when new anti-infective agents are developed, these agents are extremely expensive and available only to a limited patient population.
P. aeruginosa is another problematic pathogen that is difficult to treat because of its resistance to antibiotics. It is often acquired in the hospital and causes severe respiratory tract infections. P. aeruginosa is also associated with high mortality in patients with cystic fibrosis, severe burns, and in AIDS patients who are immunosuppressed. The clinical problems associated with this pathogen are many, as it is notorious for its resistance to antibiotics due to the permeability barrier afforded by its outer membrane lipopolysaccharide (LPS). The tendency of P. aeruginosa to colonize surfaces in a biofilm phenotype makes the cells impervious to therapeutic concentrations of antibiotics.
Another problem with conventional anti-infective agents is that some patients are allergic to the very compounds necessary to their treat their infection. For these patients, only few drugs might be available to treat the infection. If the patient is infected with a strain of bacteria that does not respond well to substitute therapies, the patient's life can be in danger.
A separate problem related to conventional treatment of surface or subsurface infections is that the infective agent interferes with the circulation of blood within the infected region. It is sometimes the case that the infective agent causes constriction of the capillaries or other small blood vessels in the infected region which reduces bloodflow. When bloodflow is reduced, a lower level of anti-infective agent can be delivered to the infected region. In addition, the infection can take a much longer time to heal when bloodflow is restricted to the infected area. This increases the total amount of drug that must be administered to the patient, thereby increasing the cost of using such drugs. Topical agents may sometimes be applied over the infected region. However, topical anti-infective agents do not penetrate deep within the skin where a significant portion of the bacteria often reside. Topical treatments of anti-infective agents are often less effective at eliminating infection than systemic administration (i.e., oral administration) of an anti-infective pharmaceutical.
In addition, despite recent advances in chronic wound care, many lower extremity ulcers do not heal. Chronic ulcers of the lower extremities are a significant public health problem. Besides the large financial burden placed on the health care system for their treatment, they cause a heavy toll in human suffering. As the population ages and with the current obesity crisis in North America, venous, diabetic, and pressure ulcers are likely to become ever more common. Approximately 4 million (1% of population) people in the United States develop chronic lower leg ulcers, the majority classified as diabetic or venous leg ulcers, and this number can climb to 4%-5% in older (>80 years of age) patients.
Aside from infection, a variety of factors can potentially influence wound healing of chronic ulcers. These include excessive exudate, necrotic tissue, poor tissue handling, and impaired tissue perfusion, as well as from clinical conditions such as advanced age, diabetes, and steroid administration.
Exudate is a clear, straw colored liquid produced by the body in response to tissue damage. Although exudate is primarily water, it also contains cellular materials, antibodies, nutrients and oxygen. In the immediate response to an injury, exudate is produced by the body to flush away any foreign materials from the site. It then is the carrier for polymorphs and monocytes so that they may ingest bacteria and other debris. Exudate also enables the movement of these phagocytic cells within the wound to help clean it as well as enables the migration of epithelial cells across the wound surface.
While exudate is an important component of wound healing, too much of it in response to chronic inflammation can worsen a wound as the enzymes in the fluid can attack healthy tissues. This may exacerbate the failure of the wound to close as well as place additional psychological pressure on the patient. Chronic wounds frequently have excessive exudate, usually associated with a chronic infection and/or biofilm that has upregulated the inflammatory cells of the body. This may be a local response or may include a systemic increase in inflammatory markers and circulating cytokines.
Chronic wounds also lead to the formation of necrotic tissue, which in turn lead to growth of microbes. Debridement of necrotic tissue is deemed as an important wound bed preparation for successful wound healing. Sharp and surgical debridement rapidly remove necrotic tissue and reduce the bacterial burden, but also carry the greatest risk of damage to viable tissue and require high levels of technical skill. Chemical, mechanical and autolytic debridement are frequently regarded as safer options, although the risk to the patient of ongoing wound complications is greater.
Additionally, the collagenase family of Metalloproteinases (MMP's) are a class of enzymes which are able to cleave native collagen into fragments. These fragments may then spontaneously denature into gelatin. Gelatin peptides are further cleaved by gelatinases such as MMP-2. Since the dry weight of skin is composed of 70-80% collagen, and since necrotic tissue is anchored to the wound bed by collagen fibers, enzymes which cleave collagen may be beneficial and assist in the debridement of this tissue. However, in chronic non-healing wounds, the levels and activity of collagenases are insufficient for the removal of necrotic tissue. Jung K, Knoll A G, Considerations for the use of Clostridial collagenase in clinical practice. Clin Drug Invest 1998; 15:245-252. Also, wound fluid from diabetics, for example, may have decreased MMP-2 activity. Furthermore, while exogenous application of collagenase has been proposed, its application suffers from the drawback of not being selective and risk the cleavage of collagen anchoring healthy cells in addition to necrotic tissue.
In the 1980's, it was discovered by researchers that the endothelium tissue of the human body produced nitric oxide (NO), and that NO is an endogenous vasodilator, namely, an agent that widens the internal diameter of blood vessels. NO is most commonly known as an environmental pollutant that is produced as a byproduct of combustion. At low concentrations such as less than 100 ppm, researchers have discovered that inhaled NO can be used to treat various pulmonary diseases in patients. For example, NO has been investigated for the treatment of patients with increased airway resistance as a result of emphysema, chronic bronchitis, asthma, adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).
While NO has shown promise with respect to certain medical applications, delivery methods and devices must cope with certain problems inherent with gaseous NO delivery. First, exposure to high concentrations of NO may be toxic, especially exposure to NO in concentrations over 1000 ppm. Even lower levels of NO, however, can be harmful if the time of exposure is relatively high. For example, the Occupational Safety and Health Administration (OSHA) has set exposure limits for NO in the workplace at 25 ppm time-weighted averaged for eight (8) hours. It is extremely important that any device or system for delivering NO include features that prevent the leaking of NO into the surrounding environment. If the device is used within a closed space, such as a hospital room or at home, dangerously high levels of NO can build up in a short period of time. One concern over NO toxicity is the binding of NO, when absorbed into the circulation system such as through inhalation, to hemoglobin that give rise to methemoglobin
Another problem with the delivery of NO is that NO rapidly oxidizes in the presence of oxygen to form NO2, which is highly toxic, even at low levels. If the delivery device contains a leak, unacceptably high levels NO2 of can develop. In addition, to the extent that NO oxidizes to form NO2, there is less NO available for the desired therapeutic effect. The rate of oxidation of NO to NO2 is dependent on numerous factors, including the concentration of NO, the concentration of O2, and the time available for reaction. Since NO will react with the oxygen in the air to convert to NO2, it is desirable to have minimal contact between the NO gas and the outside environment.
Accordingly, there is a need for a device and method for the treatment of surface and subsurface infections and wounds by the topical application of NO. The device is preferably leak proof to the largest extent possible to avoid a dangerous build up of NO and NO2 concentrations. In addition, the device should deliver NO to the infected region of the patient without allowing the introduction of air that would otherwise react with NO to produce NO2. The application of NO to the infected region preferably decreases the time required to heal the infected area by reducing pathogen levels. The device preferably includes a NO and NO2 absorber or scrubber that will remove or chemically alter NO and NO2 prior to discharge of the air from the delivery device.